Acanthopanax koreanum Nakai (Araliaceae), which is found indigenously in Cheju Island, the Republic of Korea, has been used traditionally as remedies for neuralgia, paralysis, lumbago, etc. Various useful components, including acanthoic acid of the following formula (A), have been isolated from its root bark(Kim Y. H. and Chung, B. S., J. Nat. Pro., 51, 1080(1988)). ##STR1##
Acanthoic acid has been reported to have various pharmacological effects, e.g., analgesic and anti-inflammatory activity which is due to its ability to inhibit the leukocyte migration and prostaglandin E.sub.2 (PGE.sub.2) synthesis, and to exhibit very low toxicity, e.g., 1000 mg/kg of minimum lethal dose(MLD) when administered to a rat(Lee, Y. S., "Pharmacological Study for (-)-Pimara-9(11),15-Diene-19-oic Acid, A Component of Acanthopanax koreanum Nakai", doctorate thesis, Dept. of Pharmacy, Seoul National University, Korea, 1990).
As is well known, IL-1 is a regulatory factor which participates in a wide range of human defensive and immune mechanisms(see, e.g., Dinarello, D. A., FASEB J., 2, 108 (1988)). IL-1, first discovered to be produced by activated macrophages, is produced and secreted by various cells, e.g., fibroblasts, keratinocytes, T cells, B cells, and astrocytes of brain; and has been reported to have various functions including: stimulating the proliferation of CD4+T cells(Mizel, S. B., Immunol. Rev., 63, 51(1982)); stimulating the cell-killing effect of thymic T.sub.c cells through its binding to a T cell receptor(TCR)(McConkey, D. J., et al., J. Biol. Chem., 265, 3009(1990)); inducing the production of various materials participating in the inflammatory mechanisms, e.g., PGE.sub.2, phospholipase A.sub.2 (PLA.sub.2), and collagenase(Dejana, E., et al., Bolid, 69, 695-699 (1987)); inducing the production of acute-phase proteins in liver(Andus, T., et al., Eur. J. Immunol., 123, 2928(1988)); raising blood pressure in the vascular system(Okusawa, S., et al., J. Clin. Invest., 81, 1162(1988)); inducing the production of other cytokines, e.g., IL-6 and TNF(Dinarello, C. A., et al., J. Immunol., 139, 1902(1987)), etc.
As has been reported, IL-1 relates to various immune diseases, e.g., rheumatoid arthritis(Nouri, A. M., et al., Clin. Exp. Immunol., 58, 402(1984)), rejection mechanisms after the kidney transplantation(Mauri and Teppo, Transplantation, 45, 143(1988)), and septicemia(Cannon, J. G., et al., Lymphokine Res., 7, 457(1988)). IL-1 has been also reported to induce a fever and pain when administered in a large amount to a human body(Smith, J., et al., Am. Soc. Clin. Oncol., 9, 710(1990)).
TNF-.alpha., first discovered in a serum of an animal treated with BCG(Bacille Calmette-Guerin) or LPS(lipopolysaccharide) (Carswell, E. A., et al., Proc. Natl. Acad. Sci. U.S.A., 72, 3666(1975)), has been reported to be produced by various cells, e.g., activated macrophages and fibroblasts. Further, TNF-.alpha. has been reported to have the functions of: killing the fibrosarcoma L929 cells(Espevik and Nissen-Meyer, J. Immunol. Methods, 95, 99(1986)); stimulating the proliferation of fibroblasts(Sugarman, B. J., et al., Science, 230, 943(1985)); inducing the production of PGE.sub.2, arachidonic acid, etc. which may be involved in inflammatory responses(Suttys, et al., Eur. J. Biochem., 195, 465(1991)); inducing the production of IL-6 or other growth factors(Van Hinsbergh, et al., Blood, 72, 1467(1988)), etc.
TNF-.alpha. has been also reported to participate, directly or indirectly, in various diseases; and examples of said diseases are: infectious diseases carried by trypanosoma, strains of the genus Plasmodium, etc.(Cerami, A., et al., Immunol. Today, 9, 28(1988)); autoimmune diseases such as systemic lupus erythematosus(SLE) and arthritis(Fiers, W., FEBS, 285, 199(1991)); AIDS(Mintz, M., et al., Am. J. Dis. Child., 143, 771(1989)); septicemia(Tracey, K. J., et al., Curr. Opin. Immunol., 1, 454(1989)); and infections (Balkwill, F. R. 1989, Cytokines in Cancer Therapy, Oxford University Press).
These observations have buttressed the importance of regulating the production of IL-1 and TNF-.alpha. for the maintenance of the homeostasis of immune system in a human body and for the treatment and prophylaxis of related diseases.
Accordingly, there have been proposed numerous approaches to regulate the production of interleukins. For instance, it has been reported that the occurrence of septicemia, arthritis, inflammations, etc. in animal models can be decreased by the inhibition of IL-1 binding to its receptors by employing naturally occurring IL-1 receptor inhibitors(IL-1 Ra)(Dinarello, C. A. and Thompson, R. C., Immunol. Today, 12, 404(1991)), and there have been proposed certain methods for inhibiting the activity of IL-1 by employing particular antibodies(Giovine, D. F. S. and Duff, G. W., Immunol. Today, 11, 13(1990)). In case of IL-6, proliferation of myelocytes in a patient suffering from myeloma which is caused by an excessive secretion of IL-6 has been suppressed by employing antibodies against IL-6 or IL-6 receptor(Suzuki, H., Eur. J. Immuno., 22, 1989(1992)).
However, no substance or method has been reported to inhibit specifically the productions of IL-1 and TNF-.alpha. and, therefore, efforts have continued for the discovery of specific inhibitors against the production of IL-1 and TNF-.alpha..